Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A key factor in atherosclerosis is the retention of low density lipoprotein (LDL) in the extracellular matrix of the arterial intima, where it binds to the negatively charged glycosaminoglycan chains of proteoglycans. Oxidation may lead to modification of the lysine residues of apolipoprotein B-100 of LDL, which normally mediate the binding of LDL to glycosaminoglycans. Here, we studied whether various modes of oxidation can release LDL from heparin, a glycosaminoglycan with a strong negative charge, in vitro. We found that copper ions were unable to oxidize heparin-bound LDL particles because of their redox inactivation by the glycosaminoglycans. In contrast, myeloperoxidase and hypochlorite, a product of myeloperoxidase, were able to oxidize heparin-bound LDL, and this oxidation led to the release of the oxidized particles from heparin. When the released LDL particles were compared with the residual heparin-bound LDL particles, the released particles were more electronegative and contained more modified lysine residues than did the particles that remained bound. Because human atherosclerotic lesions contain catalytically active myeloperoxidase and (lipo)proteins modified by hypochlorite, the results suggest that myeloperoxidase-secreting monocytes/macrophages in the arterial intima can oxidize and extract LDL from the extracellular matrix with ensuing uptake by the macrophages of the oxidized and released LDL, with eventual formation of foam cells.
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PMID:Myeloperoxidase and hypochlorite, but not copper ions, oxidize heparin-bound LDL particles and release them from heparin. 1174 62

High plasma homocysteine concentrations have been found to be associated with atherosclerosis and thrombosis of arteries and deep veins. The oxidative damage mediated by hydrogen peroxide production during the metal-catalyzed oxidation of homocysteine is to date considered to be one of the major pathophysiological mechanisms for this association. In this work, a very sensitive and accurate method was employed to measure the effective production of H2O2 during homocysteine oxidation. Furthermore, the interaction of homocysteine with powerful oxidizing species (hypochlorite, peroxynitrite, ferrylmyoglobin) was evaluated in order to ascertain the putative pro-oxidant role of homocysteine. Our findings indicate that homocysteine does not produce H2O2 in a significant amount (1/4000 mole/mole ratio of H2O2 to homocysteine). Moreover, homocysteine strongly inhibits the oxidation of luminol and dihydrorhodamine by hypochlorite or peroxynitrite and rapidly reduces back ferrylmyoglobin, the oxidizing species, to metmyoglobin. All these results should, in our opinion, lead to a rethinking of the commonly held view that homocysteine oxidation is one of the main causative mechanisms of cardiovascular damage.
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PMID:Is homocysteine a pro-oxidant? 1176 8

A proposed analogy between atherosclerosis and glomerulosclerosis suggests that factors that contribute to the development of atherosclerosis, ie, oxidatively modified (lipo)proteins, may also participate in glomerular injury. Although the nature of the in vivo oxidants has not been clearly identified, increasing evidence suggested the myeloperoxidase (MPO)-H(2)O(2)-halide system to be responsible for the damage observed in leukocyte-dependent glomerulonephritis. MPO, a heme protein secreted by activated phagocytes, may generate modified/oxidized proteins in vivo via intermediate formation of hypochlorous acid (HOCl)/hypochlorite. HOCl, a reactive oxygen species and powerful oxidant, can convert (lipo)proteins into atherogenic forms in vitro and in vivo. Here we demonstrate the presence of HOCl-modified proteins in glomeruli of patients with membranous glomerulonephritis using monoclonal antibodies that do not cross-react with other oxidative modifications. Immunostaining for HOCl-modified epitopes in human minimal change glomerulopathy revealed glomeruli that were unreactive, although the number of MPO-positive cells/glomerulus was slightly increased in comparison to controls. In contrast to minimal change glomerulopathy, a pronounced infiltration of mononuclear cells/glomerulus in membranoproliferative glomerulonephritis is in line with pronounced staining for HOCl-modified epitopes. Immunostaining was detected in intracapillary cells and immune complex deposits within the glomerular basement membrane. In human membranous glomerulonephritis (Stages I to III), staining for HOCl-modified proteins was localized at the basement membrane and podocytes. Staining of serial sections revealed colocalization of HOCl-modified epitopes and MPO in glomerular peripheral basement membranes. Subsequently, tubulointerstitial staining for HOCl-modified epitopes was observed in foam cells at the border of the cytoplasm and in damaged tubular epithelia in focal advanced chronic lesions. Our results indicate that oxidative modification of the basement membrane structure by phagocyte-derived HOCl may be of importance for glomerular defects. The observed colocalization of HOCl-modified proteins and MPO in podocytes and adjacent basement membranes strengthens the assumption that the MPO-H(2)O(2)-halide system contributes to glomerular dysfunction in patients with membranous glomerulonephritis.
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PMID:Immunohistochemical detection of hypochlorite-modified proteins in glomeruli of human membranous glomerulonephritis. 1179 21

Oxidation of low-density lipoproteins (LDL) is a key process in atherogenesis, and vitamin E (alpha-tocopherol, TOH) has received attention for its potential to attenuate the disease. Despite this, the type and extent of TOH oxidation and its relationship to lipid oxidation in the vessel wall where lesions develop remain unknown. Therefore, we measured oxidized lipids, TOH, and its oxidation products, alpha-tocopherylquinone (TQ), 2,3- and 5,6-epoxy-alpha-tocopherylquinones by gas chromatography-mass spectrometry analysis in human lesions representing different stages of atherosclerosis. We also oxidized LDL in vitro to establish "footprints" of TOH oxidation product for different oxidants. The in vitro studies demonstrated that tocopherylquinone epoxides are the major products when LDL is exposed to the one-electron (ie, radical) oxidants, peroxyl radicals, and copper ions, whereas TQ preferentially accumulates with the two-electron (nonradical) oxidants, hypochlorite, and peroxynitrite. In human lesions, the relative extent of TOH oxidation was maximal early in the disease where it exceeded lipid oxidation. Independent of the disease stage, TQ was always the major oxidation product with all products together representing <20% of the total TOH present, and the oxidation product profile mirroring that formed during LDL oxidation by activated monocytes in the presence of nitrite. In contrast, oxidized lipid increased with increasing disease severity. These results suggest that two-electron oxidants are primarily responsible for TOH oxidation in the artery wall, and that the extent of TOH oxidation is limited yet substantial lipid oxidation takes place. This study may have important implications regarding antioxidant supplements aimed at preventing LDL oxidation and hence atherogenesis.
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PMID:Vitamin E oxidation in human atherosclerotic lesions. 1186 23

Dietary polyphenolics such as those in soy or red wine can have beneficial effects on the development of chronic human diseases. The mechanisms of action of isoflavones have been diverse and include their roles as weak estrogens, inhibitors of tyrosine kinase-dependent signal transduction processes and as antioxidants. Recent insights into the oxidative stress model of atherosclerosis suggest an interesting synthesis of these concepts. Sites of inflammation are associated with the formation of complex mixtures of reactive oxygen, nitrogen and halogenating species capable of modifying both endogenous biomolecules and polyphenolics. Of particular significance are the halogenation reactions mediated by myeloperoxidase that can modify key amino acids such as arginine and polyphenolics such as genistein. Hypochlorite, the reaction product of myeloperoxidase can halogenate polyphenolics to form stable derivatives with modified biological activity. Thus the in situ metabolism at sites of inflammation is unique and generates novel pharmacophores with potentially distinct modes of action from the parent compounds.
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PMID:Formation of novel bioactive metabolites from the reactions of pro-inflammatory oxidants with polyphenolics. 1201 30

Oxidative modification of lipoproteins plays an important role in atherogenesis. We investigated a variety of different oxidatively modified epitopes (malondialdehyde (MDA)-2, hydroxynonenal (HNE)-7, peroxynitrite, hypochlorite, EO-6) in parallel and compared normal vessel wall, early and advanced atherosclerotic lesions in WHHL rabbits. Early atherosclerotic lesions showed abundant intracellular staining in macrophages for all ox-epitopes, apo B and apo E; advanced lesions showed a more prominent peri- and extracellular staining for ox-epitopes, which tended to colocalize more with apo B than apo E. Hypochlorite-modified epitopes showed intense staining in all types of lesions, followed by MDA-2. Early and advanced atherosclerotic lesions differed significantly in that early stages revealed abundant cellular positivity for EO-6 and weak staining for HNE-7 modified proteins whereas the opposite was observed in advanced lesions. Nuclear factor-kappa B (NF-kappa B) was nearly exclusively detected in macrophages with no difference between early and advanced lesions. We conclude that hypochlorite-modified epitopes are abundantly present at all stages of atherogenesis. EO-6 might be a marker for early, HNE-7 a marker for advanced lesions. Colocalization of ox-epitopes with apolipoproteins further supports that oxidation of lipoproteins is one of the key mechanisms in atherogenesis. Chronic stable expression and activation of NF-kappa B could be a useful target for therapeutic interventions.
Atherosclerosis 2003 Jan
PMID:Patterns of oxidized epitopes, but not NF-kappa B expression, change during atherogenesis in WHHL rabbits. 1248 46

1. Reactive oxygen species (ROS) are known to be involved in the progression of various cardiovascular diseases. One source of ROS is activated neutrophils, which can release superoxide anion radicals and hydrogen peroxide by membrane-bound NAD(P)H oxidases. These ROS not only destroy bacteria, but may also affect mammalian tissue. In addition, hydrogen peroxide serves as a substrate for myeloperoxidase, an enzyme that is released by activated neutrophils during inflammatory processes, as seen, for instance, in reperfusion injury and atherosclerosis. Myeloperoxidase catalyses the oxidation of chloride by hydrogen peroxide, yielding hypochlorite, an extremely potent oxidant. 2. The purpose of the present study was to evaluate the effects of hypochlorite on a variety of receptor-dependent processes in rat isolated left atria and rat thoracic aorta and to compare these results with the phenomena observed after incubation with hydrogen peroxide. 3. In the presence of hypochlorite (300 micro mol/L), the positive inotropic response of alpha1-adrenoceptor stimulation by methoxamine (300 micro mol/L) was converted into a negative inotropic response. In contrast, the positive inotropic effects of the beta1/beta2-adrenoceptor agonist isoprenaline (3 micro mol/L) and endothelin (ET)-1 (100 nmol/L) remained largely unaffected. 4. The inversion of alpha1-adrenoceptor-mediated inotropy was not obtained in the presence of hydrogen peroxide (500 micro mol/L). Hydrogen peroxide did not affect the positive inotropic response of isoprenaline, but it completely abolished the inotropic effect of ET-1. 5. The effect of cardiac M2-receptor stimulation was studied in the presence of hypochlorite and hydrogen peroxide. The negative inotropic response to acetylcholine (ACh) was significantly enhanced after hypochlorite incubation compared with control. 6. In the rat thoracic aorta, endothelial function, evaluated by means of ACh-induced vasodilation, was completely abolished in the presence of hypochlorite (100 micro mol/L), but remained unaffected by treatment with the same concentration of hydrogen peroxide. 7. From these data, we conclude that hypochlorite exerts more toxic properties than its precursor hydrogen peroxide, leading to substantial physiological alterations in cardiac and vascular tissue.
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PMID:Effects of hypochlorite and hydrogen peroxide on cardiac autonomic receptors and vascular endothelial function. 1268 Aug 42

In glomerular and tubulointerstitial disease, polymorphonuclear- and monocyte-derived reactive oxygen species may contribute to oxidative modification of proteins, lipids, and nucleic acids. In part, the processes instigated by reactive oxygen species parallel events that lead to the development of atherosclerosis. Myeloperoxidase (MPO), a heme protein and catalyst for (lipo)protein oxidation is present in these mononuclear cells. The ability of MPO to generate hypochlorous acid/hypochlorite (HOCl/OCl-) from hydrogen peroxide in the presence of chloride ions is a unique and defining activity for this enzyme. The MPO-hydrogen peroxide-chloride system leads to a variety of chlorinated protein and lipid adducts that in turn may cause dysfunction of cells in different compartments of the kidney. The aim of this article is to cover and interpret some experimental and clinical aspects in glomerular and tubulointerstitial diseases in which the MPO-hydrogen peroxide-chloride system has been considered an important pathophysiologic factor in the progression but also the attenuation of experimental renal disease. The colocalization of MPO and HOCl-modified proteins in glomerular peripheral basement membranes and podocytes in human membranous glomerulonephritis, the presence of HOCl-modified proteins in mononuclear cells of the interstitium and in damaged human tubular epithelia, the inflammation induced and exacerbated by MPO antibody complexes in necrotizing glomerulonephritis, and the presence of HOCl-modified epitopes in urine following hyperlipidemia-induced renal damage in rodents suggest that MPO is an important pathogenic factor in glomerular and tubulointerstitial diseases. Specifically, the interaction of MPO with nitric oxide metabolism adds to the complexity of actions of oxidants and may help to explain bimodal partly detrimental partly beneficial effects of the MPO-hydrogen peroxide-chloride system in redox-modulated renal diseases.
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PMID:Myeloperoxidase in kidney disease. 1463 18

Scavengers of hypochlorite, a highly reactive oxidant produced by activated phagocytes, could have potential therapeutic effects in diseases in which this oxidant plays a pathogenic role. Flavonoids are polyphenolic substances present in food plants and have been extensively studied for their antioxidant properties against various free radicals. Less is known about their reactivity with hypochlorite. In this study, the hypochlorite scavenging activity of flavonoids was investigated using a microplate assay recently developed in our laboratory. This method evaluates the ability of a substance to inhibit the formation of chloramines in human serum albumin upon oxidation by hypochlorite. Thirteen flavonoids were tested. Most of them inhibited human serum albumin oxidation at micro-molar concentrations and appeared more active than Trolox, a water-soluble equivalent of vitamin E. It was observed that the greater the number of hydroxyl substitutions, the greater the scavenging activity. The 3-hydroxy substitution seemed to be particularly important for scavenging activity, whereas the presence of a 2,3-double bond in the C ring did not. Flavonoids were found to be good hypochlorite scavengers in-vitro and further information is provided about the chemical aspects important for scavenging activity. Thus, flavonoids could have beneficial effects in diseases such as atherosclerosis in which hypochlorite plays a pathogenic role.
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PMID:Hypochlorite scavenging activity of flavonoids. 1523 Oct 46

Substantial evidence supports the notion that oxidative processes participate in the pathogenesis of atherosclerotic heart disease. Major evidence for myeloperoxidase (MPO) as enzymatic catalyst for oxidative modification of lipoproteins in the artery wall has been suggested in numerous studies performed with low-density lipoprotein. In contrast to low-density lipoprotein, plasma levels of high-density lipoprotein (HDL)-cholesterol and apoAI, the major apolipoprotein of HDL, inversely correlate with the risk of developing coronary artery disease. These antiatherosclerotic effects are attributed mainly to HDL's capacity to transport excess cholesterol from arterial wall cells to the liver during 'reverse cholesterol transport'. There is now strong evidence that HDL is a selective in vivo target for MPO-catalyzed oxidation impairing the cardioprotective and antiinflammatory capacity of this antiatherogenic lipoprotein. MPO is enzymatically active in human lesion material and was found to be associated with HDL extracted from human atheroma. MPO-catalyzed oxidation products are highly enriched in circulating HDL from individuals with cardiovascular disease where MPO concentrations are also increased. The oxidative potential of MPO involves an array of intermediate-generated reactive oxygen and reactive nitrogen species and the ability of MPO to generate chlorinating oxidants-in particular hypochlorous acid/hypochlorite-under physiological conditions is a unique and defining activity for this enzyme. All these MPO-generated reactive products may affect structure and function of HDL as well as the activity of HDL-associated enzymes involved in conversion and remodeling of the lipoprotein particle, and represent clinically useful markers for atherosclerosis.
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PMID:Myeloperoxidase-mediated oxidation of high-density lipoproteins: fingerprints of newly recognized potential proatherogenic lipoproteins. 1617 72


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